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Comparison of the Ketogenic Ratio of Macronutrients With the Low-Carbohydrate Diet Score and Their Association With Risk of Type 2 Diabetes in Postmenopausal Women: A Secondary Analysis of the Women's Health Initiative.
Titcomb, TJ, Liu, B, Wahls, TL, Snetselaar, LG, Shadyab, AH, Tabung, FK, Saquib, N, Arcan, C, Tinker, LF, Wallace, RB, et al
Journal of the Academy of Nutrition and Dietetics. 2023;(8):1152-1161.e4
Abstract
BACKGROUND Previous attempts to identify low-carbohydrate diets (LCDs) in epidemiological studies relied on the LCD Score, which is unable to identify ketogenic dieters. Ketogenic ratios of macronutrients are clinical equations proposed to predict ketogenic diets; however, their utility in epidemiological studies is unknown. OBJECTIVE To determine the number of participants consuming a ketogenic diet, compare ketogenic ratios to the LCD Score, and evaluate their association with type 2 diabetes mellitus (T2DM). DESIGN Secondary analysis of the Women's Health Initiative with 17.9 ± 6.03 years of follow-up. Baseline food frequency questionnaires were used to calculate the ketogenic ratio as follows: (0.9 × grams fat + 0.46 × grams protein) / (0.1 × grams fat + 0.58 × grams protein + grams net carbohydrate), a value ≥1.5 is the minimum threshold for a ketogenic diet. PARTICIPANTS/SETTING One hundred twenty-five nine hundred eighty-two postmenopausal women without diabetes (aged 50 to 79 years) enrolled in the multicenter Women's Health Initiative observational study and clinical trials were included. MAIN OUTCOME MEASURES Risk of self-reported incident T2DM. STATISTICAL ANALYSES PERFORMED Cox proportional hazards models, adjusted for age, race, ethnicity, education, income, health insurance, relationship status, geographic region, Women's Health Initiative study component, female hormone use, smoking status, alcohol use, recreational physical activity, total energy intake, diet quality, body mass index, hyperlipidemia, and hypertension, were used to compare hazard ratios and 95% CIs for T2DM among quintiles of the ketogenic ratio. RESULTS A total of 18,775 incident cases of T2DM occurred. The median ketogenic ratio was 0.35 (interquartile range 0.28 to 0.42) and 15 individuals (0.01%) exceeded the threshold for a ketogenic diet. Higher ketogenic ratio quintiles were associated with increased risk of T2DM in a dose-dependent manner. Comparing extreme quintiles of the ketogenic ratio, the hazard ratio for diabetes was 1.24 (95% CI 1.18 to 1.31; Ptrend < 0.001) in fully adjusted models. Similarly, comparing extreme quintiles, the hazard ratio for diabetes was 1.36 (95% CI 1.29 to 1.43; Ptrend < 0.001) for the LCD Score and 1.13 (95% CI 1.07 to 1.19; Ptrend < 0.001) for the simplified ketogenic ratio in fully adjusted models. CONCLUSIONS Increasing ketogenic ratio values are associated with increased risk of T2DM and align well with LCD Scores; however, too few participants consumed a ketogenic diet to determine its association with T2DM.
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Chocolate Consumption in Relation to All-Cause and Cause-Specific Mortality in Women: The Women's Health Initiative.
Sun, Y, Liu, B, Snetselaar, LG, Wallace, RB, Shadyab, AH, Chen, GC, Shikany, JM, Manson, JE, Bao, W
Journal of the Academy of Nutrition and Dietetics. 2023;(6):902-911.e3
Abstract
BACKGROUND Chocolate contains both potentially harmful components (ie, stearic acid and added sugar) and beneficial components (ie, phenolics and flavonoids). Despite its popularity, the long-term health effects of chocolate consumption remain unclear. OBJECTIVE The aim of this study was to examine the association of chocolate consumption with all-cause and cause-specific mortality. DESIGN This was a prospective cohort study. PARTICIPANTS/SETTING This study included 84,709 postmenopausal women free of cardiovascular disease (CVD) and cancer at baseline in the observational study and clinical trials control arms of the prospective Women's Health Initiative cohort who were enrolled during 1993 through 1998. These women were followed through March 2018. MAIN OUTCOME MEASURES The outcomes included all-cause mortality and cause-specific mortality from CVD, cancer, and dementia. STATISTICAL ANALYSES PERFORMED Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) of all-cause mortality and cause-specific mortality. RESULTS During 1,608,856 person-years of follow-up (mean [SD] of 19.0 [4.2] years), 25,388 deaths occurred, including 7,069 deaths from CVD, 7,030 deaths from cancer, and 3,279 deaths from dementia. After adjustment for a variety of covariates, compared with no chocolate consumption, the HRs (95% CI) for all-cause mortality were 0.95 (0.92 to 0.98), 0.93 (0.89 to 0.96), 0.97 (0.90 to 1.04), and 0.90 (0.84 to 0.97) for <1 serving/wk, 1 to 3 servings/wk, 4 to 6 servings/wk, and ≥1 serving/d of chocolate consumption, respectively (P for trend = .02). For CVD mortality, compared with no chocolate consumption, the HRs (95% CI) were 0.96 (0.91 to 1.01), 0.88 (0.82 to 0.95), 1.06 (0.93 to 1.21), and 0.92 (0.80 to 1.05) for <1 serving/wk, 1 to 3servings/wk, 4 to 6 servings/wk, and ≥1 serving/d of chocolate consumption, respectively (P for trend =.45). For dementia mortality, compared with no chocolate consumption, the HRs (95% CI) were 0.91 (0.84 to 0.99), 0.89 (0.80 to 0.99), 0.97 (0.79 to 1.18), and 0.97 (0.80 to 1.18) for <1 serving/wk, 1 to 3 servings/wk, 4-6 servings/wk, and ≥1 serving/d of chocolate consumption, respectively (P for trend = .95). Chocolate consumption was not associated with cancer mortality. CONCLUSIONS The results suggest a modest inverse association of chocolate consumption with mortality from all causes, CVD, or dementia, specifically for moderate chocolate consumption of 1 to 3 servings/wk.
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Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE).
Lai, HTM, Imamura, F, Korat, AVA, Murphy, RA, Tintle, N, Bassett, JK, Chen, J, Kröger, J, Chien, KL, Senn, M, et al
Diabetes care. 2022;(4):854-863
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OBJECTIVE Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis. RESEARCH DESIGN AND METHODS We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged ≥18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics. RESULTS During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P ≥ 0.1). CONCLUSIONS Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
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Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.
Gaziano, L, Sun, L, Arnold, M, Bell, S, Cho, K, Kaptoge, SK, Song, RJ, Burgess, S, Posner, DC, Mosconi, K, et al
Circulation. 2022;(20):1507-1517
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BACKGROUND End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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Association of Major Dietary Protein Sources With All-Cause and Cause-Specific Mortality: Prospective Cohort Study.
Sun, Y, Liu, B, Snetselaar, LG, Wallace, RB, Shadyab, AH, Kroenke, CH, Haring, B, Howard, BV, Shikany, JM, Valdiviezo, C, et al
Journal of the American Heart Association. 2021;10(5):e015553
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Dietary recommendations for human health focusing on total protein intake without considering specific protein sources may be simplistic and insufficient. The aim of this study was to investigate whether different dietary protein sources would be differentially associated with mortality risk. The study is based on data from a large prospective cohort study with up to 18-years of follow-up to investigate the risks of all-cause and cause-specific mortality in relation to animal and plant protein intake, and major sources of dietary protein. Results indicate that intake of plant protein and substitution of animal protein with plant protein, were associated with lower risk of all-cause, cardiovascular disease, and dementia mortality. Furthermore, substitution of red meat, eggs, dairy products, or legumes with nuts was associated with lower risk of all-cause mortality. Authors conclude that their findings support the need for consideration of protein sources, in addition to the amount of protein intake, in future dietary guidelines.
Abstract
Background Dietary recommendations regarding protein intake have been focused on the amount of protein. However, such recommendations without considering specific protein sources may be simplistic and insufficient. Methods and Results We included 102 521 postmenopausal women enrolled in the Women's Health Initiative between 1993 and 1998, and followed them through February 2017. During 1 876 205 person-years of follow-up, 25 976 deaths occurred. Comparing the highest with the lowest quintile, plant protein intake was inversely associated with all-cause mortality (hazard ratio [HR], 0.91 [0.86, 0.96]), cardiovascular disease mortality (HR, 0.88 [0.79, 0.97]), and dementia mortality (HR, 0.79 [0.67, 0.94]). Among major protein sources, comparing the highest with the lowest quintile of consumption, processed red meat (HR, 1.06 [1.01, 1.10]) or eggs (HR, 1.14 [1.10, 1.19]) was associated with higher risk of all-cause mortality. Unprocessed red meat (HR, 1.12 [1.02, 1.23]), eggs (HR, 1.24 [1.14, 1.34]), or dairy products (HR, 1.11 [1.02, 1.22]) was associated with higher risk of cardiovascular disease mortality. Egg consumption was associated with higher risk of cancer mortality (HR, 1.10 [1.02, 1.19]). Processed red meat consumption was associated with higher risk of dementia mortality (HR, 1.20 [1.05, 1.32]), while consumption of poultry (HR, 0.85 [0.75, 0.97]) or eggs (HR, 0.86 [0.75, 0.98]) was associated with lower risk of dementia mortality. In substitution analysis, substituting of animal protein with plant protein was associated with a lower risk of all-cause mortality, cardiovascular disease mortality, and dementia mortality, and substitution of total red meat, eggs, or dairy products with nuts was associated with a lower risk of all-cause mortality. Conclusions Different dietary protein sources have varying associations with all-cause mortality, cardiovascular disease mortality, and dementia mortality. Our findings support the need for consideration of protein sources in future dietary guidelines.
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Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.
Sarnowski, C, Cousminer, DL, Franceschini, N, Raffield, LM, Jia, G, Fernández-Rhodes, L, Grant, SFA, Hakonarson, H, Lange, LA, Long, J, et al
Human reproduction (Oxford, England). 2021;(7):1999-2010
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STUDY QUESTION Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.
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Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.
Pennells, L, Kaptoge, S, Wood, A, Sweeting, M, Zhao, X, White, I, Burgess, S, Willeit, P, Bolton, T, Moons, KGM, et al
European heart journal. 2019;(7):621-631
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AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women.
Franceschini, N, Kopp, JB, Barac, A, Martin, LW, Li, Y, Qian, H, Reiner, AP, Pollak, M, Wallace, RB, Rosamond, WD, et al
JAMA cardiology. 2018;(8):712-720
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IMPORTANCE APOL1 genotypes are associated with kidney diseases in African American individuals and may influence cardiovascular disease and mortality risk, but findings have been inconsistent. OBJECTIVE To discern whether high-risk APOL1 genotypes are associated with cardiovascular disease and stroke in postmenopausal African American women, who are at high risk for these outcomes. DESIGN, SETTING, AND PARTICIPANTS The Women's Health Initiative is a prospective cohort that enrolled 161 838 postmenopausal women into clinical trials and an observational study between 1993 and 1998. This study includes 11 137 African American women participants who had a clinical event from enrollment to June 2014. Data analyses were completed from January 2017 to August 2017. EXPOSURES The variants of APOL1 were genotyped or imputed from whole-exome sequencing. MAIN OUTCOMES AND MEASURES Incident coronary heart disease, stroke and heart failure subtypes, and overall and cause-specific mortality were adjudicated from hospital records and death certificates. Estimated incidence rates were determined for each outcome and hazard ratios (HR) and 95% CIs for the associations of APOL1 groups with outcomes. RESULTS The mean (SD) age of participants was 61.7 (7.1) years. Carriers of high-risk APOL1 variants (n = 1370; 12.3%) had higher prevalence of hypertension, use of cholesterol-lowering medications, and reduced estimated glomerular filtration rate (eGFR). After a mean (SD) of 11.0 (3.6) years, carriers of high-risk APOL1 variants had a higher incidence rate of hospitalized heart failure with preserved ejection fraction (HFpEF) than low-risk carriers did but showed no differences for other outcomes. In adjusted models, there was a significant 58% increased hazard of hospitalized HFpEF (HR, 1.58 [95% CI, 1.03-2.41]) among carriers of high-risk APOL1 variants compared with carriers of low-risk APOL1 variants. The association with HFpEF was attenuated (HR = 1.50 [95% CI, 0.98-2.30]) and no longer significant when adjusting for baseline eGFR. CONCLUSIONS AND RELEVANCE Status as a carrier of a high-risk APOL1 genotype was associated with HFpEF hospitalization among postmenopausal women, which is partly accounted for by baseline kidney function. These findings do not support an association of high-risk APOL1 genotypes with coronary heart disease, stroke, or mortality in postmenopausal African American women.
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Comparison of the Simplified sWHI and the Standard CHS Frailty Phenotypes for Prediction of Mortality, Incident Falls, and Hip Fractures in Older Women.
Zaslavsky, O, Zelber-Sagi, S, LaCroix, AZ, Brunner, RL, Wallace, RB, Cochrane, BB, Woods, NF
The journals of gerontology. Series A, Biological sciences and medical sciences. 2017;(10):1394-1400
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BACKGROUND We compared the simplified Women's Health Initiative (sWHI) and the standard Cardiovascular Health Study (CHS) frailty phenotypes in predicting falls, hip fracture, and death in older women. METHODS Participants are from the WHI Clinical Trial. CHS frailty criteria included weight loss, exhaustion, weakness, slowness, and low physical activity. The sWHI frailty score used two items from the RAND-36 physical function and vitality subscales, one item from the WHI physical activity scale plus the CHS weight loss criteria. Specifically, level of physical function was the capacity to walk one block and scored as severe (2-points), moderate (1-point), or no limitation (0). Vitality was based on feeling tired most or all of the time (1-point) versus less often (0). Low physical activity was walking outside less than twice a week (1-point) versus more often (0). A total score of 3 resulted in a frailty classification, a score of 1 or 2 defined pre-frailty, and 0 indicated nonfrailty. Outcomes were modeled using Cox regression and Harrell C-statistics were used for comparisons. RESULTS Approximately 5% of the participants were frail based on the CHS or sWHI phenotype. The sWHI frailty phenotype was associated with higher rates of mortality (hazard ratio [HR] = 2.36, p ≤ .001) and falls (HR = 1.45, p = .005). Comparable HRs in CHS-phenotype were 1.97 (p < .001) and 1.36 (p = .03), respectively. Neither phenotype predicted hip fracture. Harrell C-statistics revealed nonsignificant differences in HRs between the CHS and sWHI frailty phenotypes. CONCLUSION The sWHI phenotype, which is self-reported and brief, might be practical in settings with limited resources.
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Incidence of hematologic malignancy and cause-specific mortality in the Women's Health Initiative randomized controlled trial of calcium and vitamin D supplementation.
Ammann, EM, Drake, MT, Haraldsson, B, Wallace, RB, Johnson, KC, Desai, P, Lin, EM, Link, BK
Cancer. 2017;(21):4168-4177
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BACKGROUND Prior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists. METHODS The authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan-Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM-specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses. RESULTS A total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65-0.99) but not HM-specific mortality (HR, 0.77 [95% CI, 0.53-1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70-1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59-1.01) and 0.46 (95% CI, 0.24-0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation. CONCLUSIONS The current post hoc analysis of data from a large and well-executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168-4177. © 2017 American Cancer Society.